The ODAC Chronicles: Part 5. Prostate cancer endpoints

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1 For reprint orders, please contact The ODAC Chronicles: Part 5. Prostate cancer endpoints When all has been said and done, more has been said than done! Expert Rev. Anticancer Ther. 5(3), (2005) Antonio J Grillo-López Neoplastic and Autoimmune Diseases Research Institute, PO Box 3797, Rancho Santa Fé, CA 92067, USA Tel.: agrillo1@aol.com Cancer endpoints The US Food and Drug Administration (FDA) has been sponsoring workshops to discuss clinical trial endpoints for a variety of malignancies. The FDA has stated that issues identified in the workshops will be further discussed before the Oncologic Drugs Advisory Committee (ODAC) of the FDA and thereafter will be detailed in FDA guidance documents. The rationale for this process, as stated by Richard Pazdur (FDA, Center for Drug Evaluation and Research [CDER]), is that by statute, the FDA can take advice related to oncology drugs only from ODAC [101]. Workshop recommendations on lung and colorectal cancers have already been presented at ODAC meetings for discussion and recommendations. The FDA s Public Workshop on Clinical Trial Endpoints in Prostate Cancer was held on June 21st and 22nd, 2004, in Bethesda (MD, USA) [102]. The agenda included the discussion of issues regarding bone scans, prostate-specific antigen (PSA), disease-free survival (DFS), progression-free survival (PFS), patientreported outcomes and other endpoints. Presentations summarizing the results of this workshop were made before the ODAC on March 3, 2005 [101]. At the end of the day, there were no concrete recommendations to the FDA either by the consultants or the committee on immediately applicable endpoints for prostate cancer clinical trials. Should we be surprised? Should we be disappointed? Should we be concerned? These are some of the questions the oncology community, patients, patient advocacy groups and others should be asking. Prostate cancer accounts for 33% of all new cancer cases in males and 10% of all deaths. Prostate cancer Heart disease, cancer and stroke are the top three causes of death. We are used to seeing the statistics year after year [1]. However, in 1999 (for the first time), cancer surpassed heart disease as a cause of death in the general population under 85 years of age. Prostate cancer accounts for 33% of all new cancer cases in males and 10% of all deaths. The good news is that, thanks to early diagnosis (in great measure due to the PSA test), approximately 90% of all prostate cancers are diagnosed in a localized stage. Nevertheless, in patients aged years old, prostate cancer is the third leading cause of death and is the second leading cause in patients over 79 years of age. Males are more likely to have invasive prostate cancer during their lifetime (17% probability, birth to death) than any other cancer. There has been significant progress in early diagnosis, surgical technique, radiotherapeutic technology and hormonal therapies. However, in the 60 years of modern chemotherapy and biologic therapy of cancer, only three such agents have been approved (TABLE 1) [103]: Estramustine Mitoxantrone Docetaxel To place this in perspective, less than 5% of all approved anticancer agents are specifically approved for the treatment of patients with prostate cancer. Even the expert consultants have had relatively limited experience conducting clinical trials in hormonerefractory prostate cancer (HRPC), at least ISSN 405

2 as reflected in their publications (TABLE 2). The FDA participants had even less experience, as expected, since they are experienced in other areas but are not prostate cancer experts. Why? Is it that we have failed to find active drugs for prostate cancer? Is it that there is little interest for the development of such agents? Is it that the clinical and regulatory hurdles are such that there is little incentive for developing drugs for prostate cancer? What can be done? What must be done? Clinical trials I cannot believe that after 60 years of research only three (mediocre) agents have been found. On the other hand, if we look at what is happening today, we find that there are only five drugs in Phase III clinical trials where an approval for prostate cancer is being pursued (excluding biphosphonates and hormonal, diagnostic, radiotherapeutic and sensitizing agents) (TABLE 1) [103]. Furthermore, there is only one ongoing Phase III study listed by the US National Cancer Institute for patients with HRPC and that is a Provenge study (TABLE 1) [2]. One of Table 1. Drugs for prostate cancer - US Food and Drug Administration-approved or Phase III biologic and chemotherapeutic agents. Brand name Generic name Emcyt Estramustine Approved 1981 Novantrone Mitoxantrone Approved 1996 Taxotere (Aventis) Xinlay (Abbott) DN-101 (Novacea) Aptosyn (OSI Pharma / Cell Pathways) Provenge Dendreon) Docetaxel Atrasentan Calcitriol Exisulind Status Class Prostate cancer indication Approval endpoints (primary) Approved 2004 Phase III completed Phase II/III completed Phase III completed Chemo/hormonal Chemo Chemo Selective endothelin-a receptor antagonist Vitamin D Selective apoptotic antineoplastic drug; GMP phosphodiesterase inhibitor APC-8015 Phase III Therapeutic vaccine utilizing recombinant prostatic acid phosphatase antigen Palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate Initial chemotherapy (in combination with corticosteroids) for treatment of patients with pain related to advanced hormone-refractory prostate cancer Androgen-independent metastatic (hormone refractory) prostate cancer hormone-refractory prostate cancer hormone-refractory prostate cancer in combination with docetaxel hormone-refractory prostate cancer in combination with docetaxel metastatic hormone-refractory prostate cancer Not available Satraplatin Phase III DNA binder (Spectrum hormone-refractory Pharmaceuticals) prostate cancer Information not available Primary palliative response: a 2-point improvement on a 6-point pain intensity scale; accompanied by a stable analgesic score; duration at least 6 weeks Overall survival; time from randomization to death (any cause) Time to disease progression Reduction in PSA levels (50% or more) from baseline Phase III study: did not meet primary endpoint of improving overall survival Phase III study D9901 completed. The prespecified 36-month final survival analysis showed a statistically significant survival benefit. Phase III study D9902B - ongoing. Endpoints: time to disease progression and time to onset of disease-related pain Time to disease progression Approved as listed by the US Food and Drug Administration [102]. See also [2,101,103], manufacturers websites and press releases. Phase III as listed by the Prostate Cancer Foundation [104]. See also [2, ], manufacturers websites and press releases. Phase III listing excludes preclinical, Phase I/II, preclinical and all hormonal agents, diagnostic agents, radiotherapeutics, sensitizers and biphosphonates. GMP: Glucose monophosphate; PSA: Prostate-specific antigen. 406 (), ()

3 Prostate cancer endpoints these studies has been completed and failed to meet its overall survival (OS) endpoint, three have time to progression (TTP) as the primary endpoint and only one has a reduction in PSA levels as the primary endpoint. In this day and age where we are witnessing a remarkable impetus for new drug development, where we are seeing a variety of new therapeutics (targeted small molecules, biologics and vaccines), where in San Diego (CA, USA) alone there are over 400 biomedical companies why are we lagging behind in the development of new therapeutic agents for HRPC? Is the paucity of Phase III trials indicative of the lack of useful agents or the lack of interest in developing new agents? Interest Most new drugs are developed by or under the sponsorship of a pharmaceutical company. The key factors in getting a company involved in the development of drugs for any type of cancer include medical need, patient population, investment required, availability of preclinical leads, probability of technical success and projected market size (sales). For HRPC the medical need is clear. The patient population is large and even larger if the indication can be expanded beyond HRPC to patients at earlier stages of the disease. The investment required (in terms of initiating an in-house program, licensing efforts and collaborations) should not be too different from that required for other cancers. The availability of preclinical leads is a function of how diligently you are seeking such leads. There are clear challenges here but none that cannot be overcome by diligence, effort and good science. Most big pharmaceutical companies today require a large market size and sales projections before they will embark in any research project. Their rule of thumb is sales in excess of US$800 million. This rule does not apply to the smaller companies as they can be successful with smaller sales numbers. In any case, market size and sales are not significant issues for HPRC drugs. Thus, the major hurdle seems to be probability of technical success. Several factors go into this equation (e.g., manufacturing, conducting the clinical trials, confirming reasonable safety and efficacy), but the most important is the probability of a regulatory approval. Critical to the approval of any new anticancer drug are the results of the Phase III trial or trials (so called pivotal trials). Their success depends directly upon the primary efficacy endpoints selected prospectively and agreed to with the FDA. Hormone-refractory prostate cancer endpoints Phase III studies in patients with HRPC might be designed to meet TTP, PFS, OS, quality of life (QoL) or other endpoints. The FDA has considered OS the gold standard. However, at ODAC meetings over the last couple of years, the committee has consistently recommended PFS or TTP as preferable to OS. The principal flaw (and there are others) of OS is that patients will receive other therapies following the experimental...in 1999 (for the first time) cancer surpassed heart disease as a cause of death in the general population... therapy and these will affect the endpoint [3]. Mitoxantrone was approved primarily on the basis of QOL. Nevertheless, improvement in QOL is not a simple endpoint to document. TTP and PFS are useful in most trials of other solid tumors but pose difficult problems in HRPC. Progression of disease is not simply measured on a computed tomography (CT) scan of the liver or nodes but must be measured in bone lesions. Although the technology is better at showing progression than response, bone scan findings are nonspecific, commonly lag behind tumor response, lag behind PSA progression and do not provide accurate determination of the time of disease progression. Additionally, there is the problem of the false-positive finding or flare on bone scans. Evidence is beginning to accumulate that in advanced prostate cancer, fluorodeoxyglucose positron emission tomography (PET) will be a good marker of treatment response. There is hope that in the future, PET imaging using metabolic markers may provide rapid, accurate evidence of treatment response but its ability to accurately determine date of progression remains to be proven. PSA, however, is simple to measure, easily repeated, reproduced accurately in different laboratories and clearly associated with the time course of disease. As a result, more patients can be enrolled in trials and trials can be completed more quickly. Nevertheless, changes in PSA values may or may not accurately reflect the effect of treatment. Richard Pazdur (FDA, CDER) has said that PSA parameters would make the best surrogate endpoint and that a sponsor intending to use a PSA-derived endpoint would be required to prospectively define that endpoint. The recommended design of a trial intended to be the basis for accelerated approval is a randomized study that incorporates an interim analysis based on the prospectively defined surrogate endpoint and a final analysis based on an established clinical benefit endpoint [102]. That is the crux of the problem what PSA parameter to use (PSA doubling time, PSA slope, 50% increase in PSA or other) and how to define it. Most of the expert consultants at the workshop and at the ODAC meeting appeared to favor PSA as an endpoint, particularly for Phase I/II studies, to show clinical activity but failed to come to consensus as to what PSA parameter to use. Then again, the purpose of these meetings (according to Pazdur) was not to attain consensus but to raise issues on endpoints. Furthermore, they almost unanimously declared the need for prospectively designed Phase III validation trials before the endpoint could be used as a fully validated endpoint for drug approvals. Bhupinder Mann (FDA, CDER) has also stated that PSA-based endpoints may be acceptable surrogates for antitumor activity of a drug, for example, in a Phase II clinical trial. However, reliable use of PSA-based endpoints as surrogates for clinical benefit in Phase III controlled clinical trials when two treatments are being compared, remains to be defined [101]. Phase III studies in the US cooperative groups take at least a year from concept to first patient treated and over 3 4 years to complete enrollment. Observation time (depending on the endpoints studied) plus data 407

4 Table 2. Prostate cancer endpoints: consultants and participants *. Name (as used in PubMed search) Parameters Raghavan D Eisenberger M Scher H Pazdur R Mann BS Griebel D Affiliation Cleveland Clinic Johns Hopkins University Memorial Sloan Kettering FDA CDER FDA CDER FDA DRUDP Specialty Medical oncology Medical oncology Medical oncology Medical oncology Medical oncology Not available Workshop X X X X X X participant ODAC consultant X X X FDA staff FDA staff FDA staff All publications 192 ( ) 111 ( ) 360 ( ) 177 ( ) 13 ( ) 7 ( ) Prostate cancer publications # Prostate cancer 7 studies ** ( ) 19 ( ) 24 ( ) First author Senior author Phase III studies Phase II studies Phase I studies Single agent Combination * FDA-sponsored workshop (June 21st, 2004 April 24th, 2005) and ODAC meeting (March 3rd, 2005); only the medical oncologists and FDA speakers are listed. See [101,102]. Statisticians, epidemiologists, surgeons, urologists and radiotherapists are not listed in this table. Publications and authorship from PubMed database search (April 24th, 2005) [105]. PubMed may not reflect a complete listing of all publications for authors included on this table. # Prostate cancer related publications including preclinical, diagnostics, therapeutics and reviews. ** Prostate cancer specific clinical trials. CDER: Center for drugs evaluation and research; DRUDP: Division of reproductive and urologic drug products; FDA: US Food and Drug Administration; ODAC: Oncologic Drugs Advisory Committee. cleanup, analysis, interpretation and reporting may take another 2 3 years. Thus, even if such validation studies were formally proposed today, it would take 6 8 years before we see the final results (and this is an optimistic scenario). Survival as an endpoint The OS endpoint was called the gold standard at the ODAC meeting [101]. Another step backwards for humankind. Surprisingly, at the end of the day s presentations, ODAC s acting chairperson (Maha Hussein) stated that The first thing I think that I heard from everyone, is that survival certainly is the gold standard, whether it is practical or not practical to reach, but clearly that is the key. This may be Hussain s opinion but I did not recall everyone saying this or agreeing with this statement. I performed a search of the meeting transcript looking for the word survival and found it had been used numerous times in the presentation of data from certain studies. However, I found only two speakers that spoke about OS as an important endpoint. The first was Bhupinder Mann (FDA, CDER), who in his presentation stated Overall survival remains one of the most meaningful endpoints in controlled clinical trials in cancer. The second was Derek Rhagavan, who in his presentation stated the key question I think that we need to address today is, should survival still be regarded as the standard and later said Survival has been the standard. It is my personal belief, supported by some data that are not yet incontrovertible, that time-dependent PSA kinetics will ultimately be a very useful surrogate of outcome... Furthermore, in the entire transcript only one other person used the term gold standard and that was myself when I said I certainly don't agree that overall survival should be the gold standard, even for front line, in the setting that we are discussing Eisenberger was most practical when he later said I hear all of the discussions, and I think what we need is to come up with a reasonable set of endpoints other than survival. OS is a deceptively tantalizing endpoint as it gives the impression of being so firm, simple, well defined and definitive that little judgment might be required in its interpretation, whereas other endpoints might appear to be more 408 (), ()

5 Prostate cancer endpoints problematic [3]. This is clearly not the case. TTP, DFS and PFS are better endpoints even though they do require the performance of CTs, bone scans or magnetic resonance images. These endpoints are not subject to the multiple factors affecting OS, particularly subsequent therapies that are unrelated to the experimental therapy under evaluation, factors that make OS a poor endpoint even for randomized and controlled clinical trials. Using OS as an endpoint has major drawbacks. These studies require more patients, more time, more resources, cost much more and delay the availability of useful anticancer agents. In other words, using OS as an endpoint prolongs clinical trials, delays cancer drug approval and is not in the better interests of all patients, current and future. For all of these reasons, OS is not a desirable endpoint for clinical trials and should be bumped from its place of honor as the gold standard. Instead, we should use endpoints with clear cause and effect when we are evaluating new anticancer agents. In the case of TTP, the cause is the biologic activity of the anticancer agent being studied and the effect is lack of progression, an effect that ends when progression occurs. Both the onset and the end of the effect are easily measured (on-study date to date when progression is identified) and occur during the study before any other therapy is administered. In the case of OS, the effect is survival duration. The cause is the biologic activity of the anticancer agent being studied as influenced by subsequent therapies and supportive care. The effect, as modified by all of these factors, ends when death occurs. Death occurs after the study has ended and patients may have gone on to other studies with experimental drugs and/or received additional conventional chemotherapy. Endpoints such as TTP, DFS and PFS are much better endpoints for clinical trials than OS. In fact, the FDA has approved more new anticancer agents in the past 15 years based on these than based on OS [4]. Why then persist in calling OS the gold standard? Why is it so difficult to understand that OS is not a good endpoint when there are so many good reasons to show it is not? Is it not obvious that we need better, practical and shorter endpoints? Questions & answers As usual, there are more questions than answers. One needs to consider whether or not the right questions have been asked and the appropriate answers requested. It is not enough to ask the right question, one must then insist on getting the appropriate answers. Consensus cannot be reached, recommendations cannot be expected unless one drives to obtain them. At the workshop, the FDA asked the right questions, among others: What PSA endpoints are worthy of consideration for use in oncology trials for recurrence? Response? Progression? [101]. However, neither the FDA nor the discussion leaders steered the experts towards consensus. Yes, achieving consensus was not the FDA s goal but the workshop could have been much more productive had the effort to reach consensus been made. As a result, the workshop was an interesting and important discussion of issues and controversies but did not go any further. The ODAC meeting followed (one gestation period later, 9 months!) and was necessary because, as stated by Richard Pazdur (FDA, CDER), by statute, the FDA can take advice related to oncology drugs only from ODAC [101]. However, even that meeting was defined by Pazdur as follows I think one of our goals is not to achieve direct consensus here, but to raise issues. If there is consensus, let us hear it, and we will be happy to take it into consideration [101]. Thus, the inevitable occurred, a lot of important controversies were aired, many key issues were discussed, no consensus was achieved and no recommendations (beyond the need for a prospective randomized study to validate PSA as an endpoint) were made; a study that, under the best of circumstances, will take 6 8 years before we see the final results (and this is an optimistic scenario). A Phase III approval study conducted after this would take another 3 4 years and a regulatory approval another year. A new drug for HRPC will not be approved under these circumstances using the validated endpoint until at least years from today. I understand the issues and controversies. What I cannot understand is the resulting inaction, the analysis paralysis that kept us from making some practical, immediately useful recommendations as to endpoints in HRPC. Are there no recommendations to be made relative to the application of PSA as an endpoint to guide the FDA and sponsors, even as an interim measure, while we wait 10 years for the results of the validation study? At one point during the ODAC meeting I said we need to take some risk. We around the table today need to take some risk and say, with what we know today (which may not be perfect, which may not be 100% validated), is there some surrogate endpoint, PSA, PSA doubling time, whatever, that can be used today while we take those 10 years to validate all of this with 100% certainty? [101]. My question went unanswered. The absence of an FDA-accepted and standard PSA endpoint creates further uncertainty and dampens interest in this area of research. It means that, as stated by Pazdur, a sponsor intending to use a PSA-derived endpoint would be required to prospectively define that endpoint. This does provide flexibility but on the other hand it will create an even greater controversy as studies are performed with different definitions for a variety of PSA endpoints. Besides, why have the sponsors defined the PSA endpoint when experts have been available to do this? The presence of an FDAaccepted and standard PSA endpoint would create confidence and drive interest in developing new drugs for HRPC. From all the data presented at the workshop and then at the ODAC meeting, I have to conclude that there must be a PSA endpoint (PSA doubling time, PSA slope, 50% increase in PSA or other) that could be acceptable today even if just on an interim basis. PSA sounds, reads and looks like it should be an endpoint today. When I see a bird that walks like a duck and swims like a duck and quacks like a duck, I call that bird a duck. Richard Cardinal Cushing Information resources Additional reference and background material can be found at the FDA s website,

6 References 1 Jemal A, Murray T, Ward E et al. Cancer statistics, Can. J. Clin. 55, (2005). 2 Current clinical trials, Oncology. CD- ROM Edition. Triple i Oncology 12(2), (2005). 3 Grillo-López AJ. The ODAC Chronicles: Part 1. My First ODAC Experience. Expert Rev. Anticancer Ther. 4(5), (2004). 4 Johnson JR, Williams G, Pazdur R. End points and united states food and drug administration approval of oncology drugs. J. Clin. Oncol. 21, (2003). Websites 101 Prostate cancer endpoints. Transcript of the 3 March 2005 meeting of the Oncologic Drugs Advisory Committee of the FDA transcripts/ t1.pdf (a) Prostate cancer endpoints. FDA backgrounder for the 3 March 2005 meeting of the Oncologic Drugs Advisory Committee of the FDA. / B1_03_00-FDA-TOC.htm (b) Prostate cancer endpoint. Slides for the 3 March 2005 meeting of the Oncologic Drugs Advisory Committee of the FDA S1_index.pdf 102 US Food and Drugs administration. FDA Public Workshop on Clinical Trial Endpoints in Prostate Cancer. June 21 and 22 (2004) Prostate Cancer Foundation. Therapeutics Database Prostate Cancer Foundation PubMed Affiliation Antonio J Grillo-López, MD Neoplastic and Autoimmune Diseases Research Institute, PO Box 3797, Rancho Santa Fé, CA 92067, USA Tel.: agrillo1@aol.com 410 (), ()